The long term goals of this program project are an understanding of an inflammatory demyelinating disease of the central nervous system (CNS) induced and associated with viral infection. To this end, the projects in this program are analyzing the mechanisms of a defined model of CNS demyelination induced by the neurotropic JHM strain (MHV-4) of mouse hepatitis virus (JHMV). This model provides a means to understand the interactions between a pathogen and host that result in either an acute or persistent CNS infection. The persistent or chronic form of this infection is associated with ongoing primary demyelination a pathology similar to that seen in multiple sclerosis. Virus can not be isolated from chronically infected animals and the demyelinating lesions eventually begin to resemble a chronic plaque in multiple sclerosis. Multiple sclerosis raises many questions related to both the role of virus in induction and the immune response in the pathogenesis of demyelination. The JHMV model provides a mechanism to address fundamental questions of viral persistence, neurotropism, and immune responses, both as protective mechanisms and as inducers of demyelination. The core principal investigators have been stable and are actively collaborating. The program consists of five projects. Theses projects include a molecular analysis of tissue and CNS specific tropism via the analysis of the virus receptor, immunological projects examining the role of the CNS as both a unique target of cell-mediated cytotoxicity and immune regulation, the role of genetic variation in escape from immune detection and persistent infection and finally a novel vector system that allows the analysis of the viral structural proteins and permits the restricted expression of viral proteins, cytokines, cytotoxic T cell inhibitors and cytokines within either the CNS or within specific subsets of CNS cells.